title: Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene.
abstract: OBJECTIVE
  To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme.
  
  
  METHODS
  Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems.
  
  
  RESULTS
  Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40000, which increased to 1:15500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme.
  
  
  CONCLUSIONS
  The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation.
authors.affiliation: Institute of Inherited Metabolic Disorders, Charles University in Prague-1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Janosík
authors.forename: Jitka
authors.initials: J
authors.lastname: Sokolová
authors.forename: Bohumila
authors.initials: B
authors.lastname: Janosíková
authors.forename: Jakub
authors.initials: J
authors.lastname: Krijt
authors.forename: Veronika
authors.initials: V
authors.lastname: Klatovská
authors.forename: Viktor
authors.initials: V
authors.lastname: Kozich
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000201:enzymology; D006224:Cricetinae; D003412:Cricetulus; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D018153:Czech Republic / Q000453:epidemiology; D004926:Escherichia coli / Q000201:enzymology; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006712:Homocystinuria / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics*; D015995:Prevalence; D017510:Protein Folding
chemical_list: D003541:Cystathionine beta-Synthase